Project Summary/Abstract Obesity, which results from prolonged imbalance between energy intake and energy expenditure, is an independent risk factor for a number of chronic diseases, including type 2 diabetes, coronary artery disease, fatty liver disease, neurodegenerative disorders, and a number of cancers. Simplistically, there are two major ways of combating obesity: to decrease energy intake or to increase energy expenditure. The recent discovery of cold-induced brown/beige fat in humans has generated a great deal of excitement for its therapeutic targeting in humans. However, our current knowledge of the signaling pathways that license thermogenesis in brown/beige adipose tissue is very limited. This application builds on our new discoveries that immune signals license the thermogenic programs in brown adipose tissue of mice. We will utilize techniques from mouse genetics, immunology, genomics, and metabolism to dissect the underlying mechanisms by which immune signals regulate thermogenesis in brown adipose tissue. The three specific questions we will address are: 1) What are the physiologic mechanisms by which immune signals license thermogenesis in brown adipocytes?, 2) What are the cellular signaling pathways by which immunity regulates uncoupled respiration in brown adipocytes?, and 3) How do immune signals regulate mitochondrial protein expression and respiration? The successful completion of these aims will provide novel insights into cellular and molecular pathways that regulate brown fat thermogenesis, thus advancing our understanding of how to therapeutically target this tissue for the treatment of human obesity and type 2 diabetes.